The present invention is directed to methods of administering to mammals including humans, compounds which are selective agonists of the retinoid receptor sites designated as RXR, and which lack substantial teratogenic activity and have substantially reduced skin toxicity. The present invention is also directed to pharmaceutical compositions adapted for administering said compounds to mammals, including humans.
Compounds which have retinoid like activity are well known in the art, and are described in numerous United States and foreign patents and in scientific publications. It is generally known and accepted in the art that retinoid like activity is useful for treating animals of the mammalian species, including humans, for curing or alleviating the symptoms and conditions of numerous diseases and conditions. In other words, it is generally accepted in the art that pharmaceutical compositions having a retinoid like compound or compounds as the active ingredient are useful as regulators of cell proliferation and differentiation, and particularly as agents for treating dermatoses, such as acne, Darier""s disease, psoriasis, icthyosis, eczema and atopic dermatitis, and for treating and preventing malignant hyperproliferative diseases such as epithelial cancer, breast cancer, prostatic cancer, head and neck cancer and myeloid leukemias, for reversing and preventing atherosclerosis and restenosis resulting from neointimal hyperproliferation, for treating and preventing other non-malignant hyperproliferative diseases such as endometrial hyperplasia, benign prostatic hypertrophy, proliferative vitreal retinopathy and dysplasias, for treating autoimmune diseases and immunological disorders (e.g. lupus erythematosus) for treating chronic inflammatory diseases such as pulmonary fibrosis, for treating and preventing diseases associated with lipid metabolism and transport such as dyslipidemias, for promoting wound healing, for treating dry eye syndrome and for reversing and preventing the effects of sun damage to skin.
The compounds developed in the prior art with retinoid like properties, are, however, not without disadvantages. Several such prior art compounds cause serious irritation when applied to the skin (which is an important mode of application for treatment of skin conditions) and cause mucotaneous toxicity when administered orally as well. Many of the prior art compounds having retinoid like activity are teratogenic. Teratogenecity or teratogenic activity can be defined as an undesirable effect of a drug on a developing fetus. It is generally accepted in the art that pregnant females, and even females who are not pregnant but in the child-bearing age should avoid teratogenic drugs.
In light of the foregoing, there is a significant need in the prior art for pharmaceutical compositions, methods of treatment and new chemical entitities which are effective for treatment of the diseases and conditions for which retinoid like compounds are usually applied, and which have reduced or no teratogenic activity and cause no significant irritation on the skin.
With respect to specific compounds or classes of compounds having retinoid like or other biological activity, the following examples are noted.
German Patent DE 3316-932 A describes 1-phenyl-2-chromanyl-propylene derivatives and sulphur and nitrogen analogs. Specific examples of this disclosure are ethyl p-[(E)-2-(4,4-dimethyl-6-chromanyl, thiochromanyl or 1,2,3,4-tetrahydro-6-quinolinyl)propenyl]-1-benzoate.
U.S. Pat. No. 4,826,984 describes benzopyranyl (chromanyl) and benzofuranyl-propenyl benzoic acids and esters thereof, an example being ethyl-p-(2-(4,4-dimethyl chroman-6-yl)-propenyl benzoate.
European EP 130 795 A discloses 4,4-dimethyl-6-chromanyl alkenyl benzoic acid derivatives, thiochromanyl and tetrahydroquinolinyl analogs. The 2 and 7 positions of the chroman, thiochroman and tetrahydroquinoline ring moieties in these compounds are not substituted.
The publication WO 8500-806 A discloses 4,4. -dimethyl-chroman-6-yl and 4,4-dimethyl-thiochroman-6-yl-ethenyl and 4,4-dimethyl-chroman-6-yl and 4,4-dimethyl-thiochroman-6-yl-propenyl benzoic acid, its esters and the corresponding thiophencarboxylic acid and other heterocyclic acid analogs. The 2 position of the chroman or thiochroman ring is unsubstituted.
The publication EP 350 846 A discloses p-(2-(3,4-dihydro-4,4-dimethyl-dihydrochroman-7-yl)-propeneyl)benzoic acid ethyl ester and related compounds.
The publication WO 8504 652 A discloses certain diaryl substituted propenyl compounds, an example being ethyl (E)-4-[2-(4-isopropylphenyl)-propenylbenzoate.
European patent EP 206 751 A discloses 2-substituted phenyl-alkenyl-quinoline derivatives as inhibitors of leukotriene synthesis. An examples of a compound of this reference are (E)-4-(3-(2-(quinolin-2-yl)-1-methylethenylphenoxy)butyric acid.
Published European patent application 0 098 591 A1 describes rodenticidal disubstituted propenyl compounds, an example of which is ethyl p-[2-(4,5,6,7-tetrahydro-4,4,7,7-tetramethylbenzo[b]thien-2-yl)propenyl benzoate, and another example is ethyl 6-[(E)-2-(4,5,6,7-tetrahydro-4,4,7,7-tetramethylbenzo[b]thien-2-yl)propenyl] nicotinate.
Great Britain Patent GB 2190-378 describes tetramethyl-tetrahydronaphthylpropenylphenol compounds, examples of which are ortho, meta or para (E)-2-(5,6i7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)propenyl)phenol.
German Patent DE 3602-473 A discloses aralkenylphenol derivatives, examples of which are (E)-1-(4-hydroxyphenyl)-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)propene and (E)-1(4-methoxyphenyl)-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)propene.
European Patent EP 176 033 A discloses isoxazolylvinyl indane and tetrahydronaphthalene derivatives, an example of which is (E)-5-[2-(3-fluoro-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)-1-propenyl]-isoxazole-3-carboxylic acid.
The publication EP 303 915 discloses indanyl and tetrahydronaphthyl and substituted phenyl propenes as retinoids, where the phenyl substituent is sulfur substitited. An example of the disclosed compounds is methyl 4-(2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl(propenyl)phenylsulphone.
European patent EP 176 032 A discloses 6-styryltetrahydro-naphthalene derivatives, examples of which are (E)-4-[2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-7-hydroxy-2-naphthalenyl)-1-propenyl]benzylalcohol, and E-4-[2-(5,8-dihydro-5,5,8,8-tetramethyl-2-naphthalenyl)-1-propenyl]benzoic acid.
European Patent EP 315 071 discloses 1-benzocycloheptenyl-2-carboxy-phenyl ethylene derivatives, an example of which is ethyl p-(E)-2-(6,7,8,9-tetrahydro-7,7-dimethyl-5H-benzocycloheptene-2-yl)propenyl benzoate.
German Patent DE 3524-199-A discloses stilbene-4-carboxylic acid derivatives, examples of which are [E-2-(3,4-diisopropylphenyl)propenyl]benzoic acid, [E-2-(3-tert-butylphenyl)propenyl]benzoic acid.
European Patent EP 245 825 describes heterocyclylalkenyl benzene derivatives, examples of which are 3-(xcex2-(4xe2x80x2-hydroxy-3xe2x80x2-methoxyphenyl)ethenyl)-5-methyl-pyrazole and 5-(xcex2-(4xe2x80x2-hydroxy-3xe2x80x2,5xe2x80x2-bis-(1,1-dimethylethyl)phenyl)-ethenyl)-5-methylpyrazole.
European Patent EP 210 929 A discloses certain 2-aryl-naphthalene derivatives useful in dermatological and ophthalmologycal medicaments. Intermediates leading to the synthesis of these compounds include certain arylethenyl benzene derivatives.
German Patent DE 3531 722 A discloses certain benzonorbornene derivatives which have vitamin A like activity.
Great Britain patent GB 2164-938 A discloses certain 2-styryl-naphthalene derivatives having retinoid like activity. An example of the compounds is 2-(4-methyl-xcex2-methyl-styryl)naphthalene.
U.S. Pat. No. 4,326,055 discloses ethene derivatives which have a substituted phenyl ring and a substituted indane or tetrahydronaphtalene group. The compounds are described as tumor inhibiting agents, and useful for treating dermatological conditions and rheumatic illnesses.
U.S. Pat. No. 4,723,028 discloses 1,2-diphenylethene (stilbene) derivatives which have retinoid like activity.
U.S. Pat. No. 4,740,519 discloses certain aromatic heterocycle derivatives which have retinoid like activity.
Published European Patent Application 0130795 discloses ethene derivatives, where the ethene moiety is substituted by a substituted phenyl group and by a substituted chroman, thiochroman or quinoline group. The compounds are useful for inhibiting the degradation of cartilage in mammals.
Several co-pending applications and recently issued patents of the present inventor, which are assigned to the assignee of the present application, are directed to further compounds having retinoid like activity and/or to methods of treatment of mammals including humans with retinoid-like compounds.
Relatively recently it was recognized in the prior art that there is more than one retinoid cellular response pathway in biological systems, and that at least two main families of receptors exist in biological systems for naturally occurring retinoid hormones. These relatively recent developments in the prior art are described in the articles: D. J. Mangelsdorf et al. xe2x80x9cNuclear receptor that identifies a novel retinoic acid response pathwayxe2x80x9d, Nature Vol 345 May 17, 1990 pp 224-229; and J. N. Rottman et al. A Retinoic Acid-responsive Element in the Apiloprotein AI Gene Distinguishes between Two Different Retinoic Acid Response Pathways, Molecular and Cellular Biology, July 1991, pp 3814-3820. The following additional references relate to retinoic acid receptors. M. Petkovich et al. xe2x80x9cA human retinoic acid receptor which belongs to the family of nuclear receptorxe2x80x9d, Nature, Vol. 330, Dec. 3, 1987, pp 444-450; V. Giguere et al. xe2x80x9cidentification of a receptor for the morphogen retinoic acidxe2x80x9d, Nature, Vol 330, Dec. 17, 1987, pp 624-629; N. Brand et al. xe2x80x9cIdentification of a second human retinoic acid receptorxe2x80x9d, Nature, Vol 332, Apr. 28, 1988, pp 850-853; A. Krast et al., xe2x80x9cA third human retinoic acid receptor, hRARxe2x80x9d, Proc. Nat""l. Acad. Sci. USA, Vol 86, July 1989, pp 5310-5314; D. J. Mangelsdorf et al., xe2x80x9cCharacterization of three RXR genes that mediate the action of 9-cis-retinoic acidxe2x80x9d, Genes and Development, Vol. 6, 1992, pp. 329-344.
The two main families of retinoid receptors are termed RAR (Retinoic Acid Receptor) and RXR (Retinoid X Receptor) in the art, and each of these two families is known to have subtypes, which are designated by letters of the Greek alphabet, such as RARxcex1, RARxcex2 and RARxcex3. The above-noted article by D. J. Mangelsdorf et al. states that some retinoid-like compounds (retinoic acid analogues) activated the RAR receptors much more strongly than the RXR receptors.
It has been discovered in accordance with the present invention that retinoid-like compounds which act selectively, and preferably even specifically as agonists of the RXR receptor sites in preference over the RAR receptor sites, possess desirable therapeutic properties associated with retinoids but without having one or more undesirable side effects of retinoids, such as teratogenecity or skin toxicity. For the purposes of the present invention, a compound is defined to be a specific or at least selective agonist of the RXR receptor site if the compound is at least approximately ten times more potent as an agonist at the RXR receptor sites than at the RAR receptor sites.
Accordingly, the present invention relates to methods of treating animals of the mammalian species, including humans, and particularly females of child-bearing age and pregnant females, with a non-teratogenic pharmaceutical composition comprising one or more specific or selective RXR agonist retinoid-like compounds as the active ingredient, for treatment of the diseases or conditions against which retinoid like compounds are useful, namely as regulators of cell proliferation and differentiation, and particularly as agents for treating dermatoses, such as acne, Darier""s disease, psoriasis, icthyosis, eczema and atopic dermatitis, and for treating and preventing malignant hyperproliferative diseases such as epithelial cancer, breast cancer, prostatic cancer, head and neck cancer and myeloid leukemias, for reversing and preventing atherosclerosis and restenosis resulting from neointimal hyperproliferation, for treating and preventing other non-malignant hyperproliferative diseases such as endometrial hyperplasia, benign prostatic hypertrophy, proliferative vitreal retinopathy and dysplasias, for treating autoimmune diseases and immunological disorders (e.g. lupus erythematosus) for treating chronic inflammatory diseases such as pulmonary fibrosis, for treating and preventing diseases associated with lipid metabolism and transport such as dyslipidemias, for promoting wound healing, for treating dry eye syndrome and for reversing and preventing the effects of sun damage to skin.
The present invention is also directed to the pharmaceutical compositions used in the above-noted methods of treatment.
The present invention particularly covers methods for treating diseases and conditions where retinoid like compounds are effective for treatment, but their use is limited because of their generally known teratogenecity or skin toxicity.